bims-ciryme Biomed News
on Circadian rhythms and metabolism
Issue of 2025–02–09
eight papers selected by
Gabriela Da Silva Xavier, University of Birmingham
  1. Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation.
  2. Markovian State Models uncover Casein Kinase 1 dynamics that govern circadian period.
  3. The liver clock tunes transcriptional rhythms in skeletal muscle to regulate mitochondrial function.
  4. Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB.
  5. Parameterized resetting model captures dose-dependent entrainment of the mouse circadian clock.
  6. The Regulatory-associated protein of target of rapamycin 1B (RAPTOR 1B) interconnects with the photoperiod pathway to promote flowering in Arabidopsis.
  7. A daily rhythm of cell proliferation in a songbird brain.
  8. BMAL1 rescued the hippocampus-dependent recognition memory induced by sleep deprivation.
  1. Proc Natl Acad Sci U S A. 2025 Feb 11. 122(6): e2411916122
    Circadian clock control of interactions between eIF2α kinase CPC-3 and GCN1 with ribosomes regulates rhythmic translation initiation.
    Ebimobowei O Preh, Manuel A Ramirez, Sidharth Mohan, Chanté R Guy, Deborah Bell-Pedersen.
      Misregulation of the activity of GCN2, the kinase that phosphorylates and inactivates translation initiation factor eIF2α, has been implicated in several health disorders, underscoring the need to determine the mechanisms controlling GCN2 activation. During nutrient starvation, increased uncharged tRNA levels trigger GCN1 and GCN20 proteins to mediate the binding of uncharged tRNA to GCN2 to activate the kinase to phosphorylate eIF2α. Under constant conditions, activation of the Neurospora crassa homolog of GCN2, CPC-3, is controlled by the circadian clock. However, how the circadian clock controls the rhythmic activity of CPC-3 was not known. We found that the clock regulates CPC-3 and GCN1 interaction with ribosomes and show that these interactions are necessary for clock regulation of CPC-3 activity. CPC-3 activity rhythms, and the rhythmic interaction of CPC-3 and GCN1 with ribosomes, are abolished in a temperature-sensitive valyl-tRNA synthetase mutant (un-3ts) that has high levels of uncharged tRNAVal at all times of the day. Disrupting the interaction between GCN1 and uncharged tRNA in the absence of GCN20 altered rhythmic CPC-3 activity, indicating that the clock controls the interaction between uncharged tRNA and GCN1. Together, these data support that circadian rhythms in mRNA translation through CPC-3 activity require rhythms in uncharged tRNA levels that drive the rhythmic interaction between CPC-3 and GCN1 with ribosomes. This regulation uncovers a fundamental mechanism to ensure temporal coordination between peak cellular energy levels and the energetically demanding process of mRNA translation.
    Keywords:  circadian clock; eIF2α; ribosome; tRNA synthetase; translation initiation
    DOI:  https://doi.org/10.1073/pnas.2411916122
  2. bioRxiv. 2025 Jan 22. pii: 2025.01.17.633651. [Epub ahead of print]
    Markovian State Models uncover Casein Kinase 1 dynamics that govern circadian period.
    Clarisse Gravina Ricci, Jonathan M Philpott, Megan R Torgrimson, Alfred M Freeberg, Rajesh Narasimamurthy, Emilia Pécora de Barros, Rommie Amaro, David M Virshup, J Andrew McCammon, Carrie L Partch.
      Circadian rhythms in mammals are tightly regulated through phosphorylation of Period (PER) proteins by Casein Kinase 1 (CK1, subtypes δ and ε). CK1 acts on at least two different regions of PER with opposing effects: phosphorylation of phosphodegron (pD) regions leads to PER degradation, while phosphorylation of the Familial Advanced Sleep Phase (FASP) region leads to PER stabilization. To investigate how substrate selectivity is encoded by the conformational dynamics of CK1, we performed a large set of independent molecular dynamics (MD) simulations of wildtype CK1 and the tau mutant (R178C) that biases kinase activity toward a pD. We used Markovian State Models (MSMs) to integrate the simulations into a single model of the conformational landscape of CK1 and used Gaussian accelerated molecular dynamics (GaMD) to build the first molecular model of CK1 and the unphosphorylated FASP motif. Together, these findings provide a mechanistic view of CK1, establishing how the activation loop acts as a key molecular switch to control substrate selectivity. We show that the tau mutant favors an alternative conformation of the activation loop and significantly accelerates the dynamics of CK1. This reshapes the binding cleft in a way that impairs FASP binding and would ultimately lead to PER destabilization and shorter circadian periods. Finally, we identified an allosteric pocket that could be targeted to bias this molecular switch. Our integrated approach offers a detailed model of CK1's conformational landscape and its relevance to normal, mutant, and druggable circadian timekeeping.
    Statement of Significance: Disruption of circadian rhythms alters the temporal orchestration of vital cellular processes and increases the propensity for sleep disorders, metabolic disease, and cancer. Circadian rhythms are generated by a vast gene expression program controlled at the cellular level by a molecular clock comprised of dedicated clock proteins. Amongst the essential protein characters is Casein kinase 1 (CK1), which acts on multiple clock protein substrates. A delicate balance of CK1 activity on these substrates is crucial for proper circadian timekeeping, highlighting CK1 as a promising drug target to tune clock timing. This work aims to identify the conformational landscape of CK1 that underlies its substrate specificity and provide molecular insight for pharmacologic development that could modulate CK1 function for those suffering from clock-related syndromes.
    DOI:  https://doi.org/10.1101/2025.01.17.633651
  3. bioRxiv. 2025 Jan 20. pii: 2025.01.17.633623. [Epub ahead of print]
    The liver clock tunes transcriptional rhythms in skeletal muscle to regulate mitochondrial function.
    Valentina Sica, Tomoki Sato, Ioannis Tsialtas, Sophia Hernandez, Siwei Chen, Pierre Baldi, Pura Muñoz Cánoves, Paolo Sassone-Corsi, Kevin B Koronowski, Jacob G Smith.
      Circadian clocks present throughout the brain and body coordinate diverse physiological processes to support daily homeostasis and respond to changing environmental conditions. The local dependencies within the mammalian clock network are not well defined. We previously demonstrated that the skeletal muscle clock controls transcript oscillations of genes involved in fatty acid metabolism in the liver, yet whether the liver clock also regulates the muscle was unknown. Here, we use hepatocyte-specific Bmal1 KO mice (Bmal1 hep-/- ) and reveal that approximately one third of transcriptional rhythms in skeletal muscle are regulated by the liver clock vivo. Treatment of myotubes with serum harvested from Bmal1 hep-/- mice inhibited expression of genes involved in metabolic pathways, including oxidative phosphorylation. Overall, the transcriptional changes induced by liver clock-driven endocrine-communication revealed from our in vitro system were small in magnitude, leading us to surmise that the liver clock acts to fine-tune metabolic gene expression in muscle. Strikingly, treatment of myotubes with serum from Bmal1 hep-/- mice inhibited mitochondrial ATP production compared to WT and this effect was only observed with serum harvested during the active phase. Overall, our results reveal communication between the liver clock and skeletal muscle-uncovering a bidirectional endocrine communication pathway dependent on clocks in these two key metabolic tissues. Targeting liver and muscle circadian clocks may represent a potential avenue for exploration for diseases associated with dysregulation of metabolism in these tissues.
    DOI:  https://doi.org/10.1101/2025.01.17.633623
  4. Commun Biol. 2025 Feb 07. 8(1): 191
    Drosophila ubiquitin-specific peptidase 14 stabilizes the PERIOD protein by regulating a ubiquitin ligase SLIMB.
    So Who Kang, Jung-Eun Park, Soonhyuck Ok, Minhui Um, Hyeonjeong Son, Seunghee Byun, Nayoung Park, Su Jin Lee, Thị Xuân Thùy Trần, Gyeongmin Kim, Jeonghun Yeom, Kyunggon Kim, Eun Young Kim, Min-Ji Kang.
      The circadian clock orchestrates behavior and physiology through the oscillation of key clock proteins like PERIOD (PER). Here, we investigate the role of ubiquitin-specific peptidase 14 (USP14) in modulating PER stability and circadian rhythms in Drosophila. We find that overexpression of USP14 in clock cells reduces PER protein levels without altering its mRNA levels whereas USP14 knockdown increases PER protein levels, suggesting that USP14 regulates PER post-translationally. Interestingly, despite these alterations in PER levels, neither USP14 overexpression nor knockdown significantly impacts circadian behavioral rhythms, likely because of slight effects on PER levels in small ventral lateral neurons (sLNvs). Further analysis shows that USP14 physically interacts with Supernumerary Limbs (SLIMB), a protein involved in PER degradation. Moreover, reducing slimb expression mitigates the effects of USP14 on PER protein stability. Mass spectrometry identifies two ubiquitination sites on PER (Lys1117 and Lys1118) critical for its degradation. Expression of PER1117A, 1118A mutant in per01 background impairs circadian rhythm strength. In conclusion, this study demonstrates that Drosophila USP14 indirectly modulates PER protein stability by affecting SLIMB and highlights the critical role of specific ubiquitination sites on PER in maintaining circadian rhythms.
    DOI:  https://doi.org/10.1038/s42003-025-07632-9
  5. Nat Commun. 2025 Feb 06. 16(1): 1421
    Parameterized resetting model captures dose-dependent entrainment of the mouse circadian clock.
    Kosaku Masuda, Ryusuke Yoshimoto, Ruoshi Li, Takeshi Sakurai, Arisa Hirano.
      The phase response curve (PRC) represents the time-dependent changes in circadian rhythm phase following internal or external stimuli. However, this time dependence complicates PRC measurement and quantification owing to its variable shape with changing stimulus intensity. Our previous work demonstrated that resetting a desynchronized circadian clock (singularity response, SR) simplifies the analysis by requiring only amplitude and phase parameters. In this study, we construct a comprehensive model for phase resetting in the mouse circadian clock by converting PRCs into SR parameters. We analyze single-cell PRCs and show that the SR amplitude parameters for different stimulus concentrations follow the Hill equation. Additionally, the model predicts the combined effects of multiple stimuli and pre-treatment (background) on phase response by simple addition or subtraction of individual SR parameters. Experimental validation using SR measurements in mouse cells and tissues confirms the model's accuracy. This study demonstrates that SRs facilitate PRC quantification and reveal simple rules governing phase resetting properties under various conditions using SR parameters.
    DOI:  https://doi.org/10.1038/s41467-025-56792-z
  6. Proc Natl Acad Sci U S A. 2025 Feb 11. 122(6): e2405536122
    The Regulatory-associated protein of target of rapamycin 1B (RAPTOR 1B) interconnects with the photoperiod pathway to promote flowering in Arabidopsis.
    Reynel Urrea-Castellanos, Maria J Calderan-Rodrigues, Anthony Artins, Magdalena Musialak-Lange, Appanna Macharanda-Ganesh, Alisdair R Fernie, Vanessa Wahl, Camila Caldana.
      The transition from vegetative to reproductive growth, or floral transition, is a tightly regulated, energy-demanding process. In Arabidopsis, the interplay of light perception and circadian rhythms detects changes in photoperiod length, accelerating flowering under long days (LD). CONSTANS (CO), a transcription factor, upregulates FLOWERING LOCUS T (FT) in leaves during dusk. The FT protein then moves to the shoot apical meristem, triggering the floral transition. While light and circadian signals control CO protein levels, less is known about how the nutrients/energy sensing regulates the photoperiod pathway for flowering modulation in this process. In our study, we identify the contribution of the Regulatory-associated protein of target of rapamycin 1B (RAPTOR1B), a component of the nutrient-sensing TOR complex (TORC), in the induction of specific flowering genes under CO control. While transcription of CO remains unaffected in raptor1b mutants, a reduction in its protein levels at dusk is observed compared to the wild type. Remarkably, the mutant also exhibits compromised GIGANTEA (GI) protein levels, crucial for CO stabilization during dusk. Our results indicate that the interaction and colocalization of RAPTOR1B with GI in the nucleus might influence GI levels through an unknown posttranscriptional mechanism. Genetic crosses position RAPTOR1B upstream of CO and GI. This is supported by phenotypic and molecular analyses. Our findings demonstrate that RAPTOR1B, likely as part of TORC, contributes to the photoperiod pathway of the flowering network, ensuring the timely initiation of floral transition under LD conditions.
    Keywords:  GIGANTEA; RAPTOR1B; TOR pathway; flowering; photoperiod
    DOI:  https://doi.org/10.1073/pnas.2405536122
  7. Sci Rep. 2025 Feb 08. 15(1): 4685
    A daily rhythm of cell proliferation in a songbird brain.
    Vladimira Hodova, Valentina Maresova, Rebecca Radic, Lubica Kubikova.
      Neurogenesis is an active process of creating new neurons in the neurogenic zone. It is influenced by many factors, including the circadian system, which is synchronized by light. Neurogenesis in laboratory rodents peaks at night, and the rodents are nocturnal, contrary to humans that are active during the day. Here, we studied whether proliferation and apoptosis exhibit a daily rhythm in the brain of the diurnal songbird zebra finch (Taeniopygia guttata) and whether the cell proliferation peaks during the dark phase of the day, as in rodents. We injected the birds with the cell proliferation marker 5-ethynyl-2´-deoxyuridine (EdU; thymidine analog), quantified the number of dividing cells in the neurogenic ventricular zone (VZ), and measured mRNA expression of clock genes as well as genes indicating cell proliferation or apoptosis. First, we confirmed the daily rhythms of the clock genes. Next we found that proliferation along the whole VZ did not exhibit a daily rhythm. However, proliferation in the central ventral part of the VZ, i.e. "the hot-spot" area, showed a daily rhythm of proliferation. The highest number of newborn cells was detected in the dark phase of the day. The relative expression of the apoptotic genes caspase 3, Bcl-2, and Bax as well as the proliferating cell nuclear antigen (PCNA) did not show any rhythm. In summary, our results show that cell proliferation in the "hot-spot" region of the VZ in diurnal songbirds shows rhythmic activity over a period of 24 h and that the maximum cell proliferation occurs in the passive phase. This study may have implications for understanding the mechanisms underlying the daily regulation of brain cell proliferation in different species.
    Keywords:  Circadian rhythm; Clock genes; EdU; Neurogenic; QPCR; Ventricular zone
    DOI:  https://doi.org/10.1038/s41598-025-88957-7
  8. Neuroscience. 2025 Feb 02. pii: S0306-4522(25)00083-1. [Epub ahead of print]569 1-11
    BMAL1 rescued the hippocampus-dependent recognition memory induced by sleep deprivation.
    Xiao Li, Qian Zheng, Honghong Yu, Tingting Du, Tian Hu, Lanyue Gao, Lihong Jia, Qi Sun.
      Sleep plays an important role in the process of memory. This study investigated the role of the circadian clock gene, BMAL1 of the master circadian clock in mediating the impairment of hippocampus-dependent recognition memory caused by sleep deprivation. After 4 weeks of sleep deprivation, the novel object recognitiontask was used to evaluate the recognition memory of mice, the expression levels of circadian clock genes, and Nrf2 and PKA/CREB/BDNF signal pathways were detected by Western blot, Realtime-qPCR, and immunofluorescence. The mice in the SD group exhibited a significant decrease in the duration of exploration of novel objects. The protein expression levels of PER1, PER2, CLOCK, and BMAL1, and PKA/CREB/BDNF pathway in the hippocampus of the SD group were significantly reduced, and the Nrf2-mediated anti-oxidative capacity was also compromised in the SD group. Moreover, these aberrations could be mitigated through compensation with BMAL1 in the SCN of the hypothalamus. Sleep deprivation resulted in a reduction in the expression of the core clock gene BMAL1 in the hippocampus, leading to an imbalance in the antioxidant system and damaging down-regulating the PKA/CREB/BDNF signal pathway that related to the proteins associated with recognition memory in the hippocampal synapse plasticity and oxidative stress, which could be reversed by overexpression compensation of BMAL1 in the SCN that might rely on the multi-synaptic neural projections to the hippocampus.
    Keywords:  BMAL1; Hippocampus-dependent memory; Oxidative stress; Sleep deprivation; Synaptic plasticity
    DOI:  https://doi.org/10.1016/j.neuroscience.2025.01.067
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